1. Field of the Invention
This invention is a method for inhibiting the neuropeptide Y (xe2x80x9cNPYxe2x80x9d) Y5 receptor using a class of amide derivatives. As antagonists of the Y5 receptor, the amide derivatives are useful in treating obese mammals, mammals with bulimia, for treating mammals with obesity related disorders including, but not limited to type II diabetes, insulin resistance hyperlipidemia, hypertension, polycystic ovarian disease, pulmonary disease, sleep apnea, and for treating mammals suffering from NPY Y5 receptor inhibition related disorders such as memory disorders, epilepsy, dyslipidemia, and depression.
2. Description of the Art
NPY is a 36 amino acid peptide that is a member of a larger peptide family which includes peptide YY (PYY), and pancreatic peptide (PP). NPY is highly conserved in a variety of animal, reptile and fish species and is found mainly in the central and peripheral sympathetic neurons. Furthermore, NPY is the most prevalent peptide in the mammalian brain where it is found primarily in the limbic regions. NPY has been found to elicit a number of physiological responses including appetite stimulation, anxiolysis, hypertension, and regulation of coronary tone.
NPY is believed to stimulate food intake by activating a hypothalamic eating receptor. Hu et al., J. Bio. Chem., Vol. 271, No. 42 pp.26315-319 (1996) discloses the isolation and identification and the expression cloning of a novel Y-type receptor from rat hypothalamus which the authors designated Y5. According to Hu et al., the localization of Y5 mRNA in critical areas of the brain hypothalamus and other brain regions known to regulate food intake together with an in vitro pharmacological profile consistent with the in vivo feeding data leads those skilled in the art to believe that the Y5 receptor is a primary mediator of NPY-induced feeding. A human homologue of the Y5 receptor has also been identified by Gerald et al., Nature, 382:168-171 (1996) which discloses the isolation, expression and analysis of an NPY Y5 receptor from the rat hypothalamus.
Antagonists of NPY receptors other than the Y5 receptors have been identified. For example, U.S. Pat. No. 5,554,621 discloses NPY antagonists that act on the Y1, Y2, Y3 and other Y1-like or Y4-type receptors. The reported antagonists are dihydropyridine based substituents.
U.S. Pat. No. 5,506,248 also discloses NPY receptor antagonists. The compositions disclosed each include sulphamadyl and amidino radicals. The disclosed compositions do not include amide moieties.
WO 96/16542 discloses genetically modified NPY receptors.
There is evidence that the Y5 receptor of NPY has a pharmacological feeding profile that is unique in comparison to other NPY receptors, namely, Y1, Y2, Y3 and Y4/PP1 because the Y5 receptor response correlates well with in vivo potencies of the standard peptides in the stimulation of feeding. Furthermore, antagonists of other NPY receptors such as Y1 do not necessarily exhibit an inhibitory response when assayed against Y5. In view of the knowledge that NPY plays an important role in eating and other disorders and in view of the knowledge that the Y5 receptor plays an important and unique role in the mechanism of such disorders, there is, therefore, a great need for antagonists of the NPY Y5 receptor. Furthermore, there is a need for antagonists of NPY that specifically target the Y5 receptor.
The present invention relates to methods for using amide derivatives that are NPY Y5 receptor antagonists to treat NPY mediated disorders including eating disorders such as bulimia and obesity. The present invention also includes novel amide derivatives. The amide derivative described immediately below, except for compounds 330-362 disclosed in Table 4 are novel, while all of the compounds described below, including compounds 137-188 disclosed in Table 4 are useful in the methods disclosed herein.
One object of this invention is a novel class of amide derivatives having the formula 
except that compounds of this invention do not include compounds 330-362 identified in Table 4.
Another object of this invention is a method for treating obesity, obesity related disorders and eating disorders in mammals using a therapeutically effective amount of a composition heretofore unknown for its NPY Y5 inhibitory properties.
It is another object of this invention to provide a method for the effective treatment of diseases that include the NPY Y5 receptor in their mechanism.
It is still another object of this invention to provide a method for the treatment of obesity and bulimia in humans using a new class of amide derivatives.
Another object of this invention are novel amide derivatives of the compound of formula (I) that are useful as NPY Y5 receptor antagonists and therapeutic compositions containing the same.
In one embodiment, this invention is a method for treating mammalian disorders mediated by the NPY Y5 receptor comprising the administration to a mammal of a therapeutically effective amount of at least one compound of formula (I) or pharmaceutically acceptable salts thereof wherein R1-R5, are each individually selected from the group of substituents including hydrogen, halogen, hydroxyl, thiol, lower alkyl, substituted lower alkyl, alkenyl, alkynyl, alkylalkenyl, alkyl alkynyl, alkoxy, alkylthio, acyl, aryloxy, amino, amido, carboxyl, aryl, substituted aryl, heterocycle, heteroaryl, substituted heterocycle, heteroalkyl, cycloalkyl, substituted cycloalkyl, alkylcycloalkyl, alkylcycloheteroalkyl, nitro, and cyano.
In another embodiment, this invention is a method for treating mammalian disorders mediated by the NPY Y5 receptor comprising the administration to a mammal of a therapeutically effective amount of at least one compound having the general formula described above.
In yet another embodiment, this invention is a pharmaceutical dosage form comprising at least one amide derivative of a compound of formula (I) and at least one pharmaceutical additive.
The present invention relates to novel compositions that are NPY Y5 receptor antagonists and methods for using the compositions to treat NPY mediated disorders including eating disorders such as bulimia and obesity. Useful compositions of this invention are amide derivatives having the formula: 
In the composition, R1-R5 are each individually selected from the group of substituents including hydrogen, halogen, hydroxyl, thiol, lower alkyl, substituted lower alkyl, alkenyl, alkynyl, alkylalkenyl, alkyl alkynyl, alkoxy, alkylthio, acyl, aryloxy, amino, amido, carboxyl, aryl, substituted aryl, heterocycle, heteroaryl, substituted heterocycle, heteroalkyl, cycloalkyl, substituted cycloalkyl, alkylcycloalkyl, alkylcycloheteroalkyl, nitro, and cyano. R1 is preferably selected from: cyclohexyl; benzoyl; phenyl; phenyl substituted at least once with a lower alkyl that is in turn substituted at least once with a substituent selected from cycloalkyl, alkoxy, furan, oxo, phenyl, diisopropylamine, alkoxy, or mixtures thereof, lower alkyl, alkyl substituted at least once by oxo, phenyl, or by mixtures thereof, phenyl substituted alkene, carboxamide, carboalkoxy, methyl substituted carbophenoxy, phenyldiazo, halogen, nitro, trifluoroalkyl, amino, phenyl substituted amino, lower alkyl substituted amino, aminoacyl, sulfonylphenyl, hydroxy, alkoxy, fluoro substituted phenyl, oxazole, phenoxy, thioalkoxy, and mixtures thereof; hydroxy or alkoxy substituted naphthyl; 1H-indazole; fluorenone; fluorene; and phenyl.
R2 is preferably hydrogen, or a lower alkyl.
R3 is preferably hydrogen or lower alkyl, phenyl, and most preferably hydrogen.
R4 is preferably hydrogen or lower alkyl, phenyl, and most preferably hydrogen or methyl.
R5 is preferably selected from substituents including: pyrrolidine; pyrrolidine substituted at least once by amino, acylamino, trifluoroacylamino, hydroxyl, carboxyl, carbobenzyloxyamino, carbomethoxyamino, carbotertbutoxyamino, alkyl substituted carbotertbutoxyamino, pyridine, lower alkyl, alkene, carboxamide, hydroxymethyl, aminoalkyl, pyrolidinemethyl, alkoxy methyl, carboxylmethyl, hydroxymethyl substituted at least once by phenyl and mixtures thereof; morpholine; piperazine substituted at least once with benzyl, phenyl, halogen substituted phenyl, and mixtures thereof; unsubstituted piperidine; substituted piperidine; piperidine substituted at least once by 2-oxo-2,3-dihydrobenzimidaz-1-ol, unsubstituted lower alkyl, lower alkyl substituted at least once by aminoethylamino, iodide, xe2x95x90O, piperidine, hydroxymethyl substituted piperidine, acylamino, hydroxyl, phenyl, and mixtures thereof, cyano, halogen, cyanomethylphenyl, piperidine, pyrolidine, carboxyl, phenyl, phenyl substituted at least once by trifluoromethyl, lower alkyl, halogen, and mixtures thereof, 4-oxo-1-phenyl-1,3,8-triazaspiro[4.5dec-8-yl], hydroxyl, alkoxy, carboxyl amide having the formula CONR8R9 wherein R8 and R9 are each individually hydrogen or lower alkyl, or R8 and R9 are united with a nitrogen atom to form a piperidine substituent, amino alkyl having the formula NR10R11 where R10 and R11 are each individually selected from lower alkyl, cycloalkyl and phenyl, a ketone having the formulaxe2x80x94COR12 where R12 is phenyl substituted by halogen or alkoxy or mixtures thereof; 3,6-dihydro-2H-pyridin-1-yl; halogen substituted phenyl substituted 3,6-dihydro-2H-pyridin-1-yl; 1,3,3-trimethyl-6-aza-bicyclo[3.2.1]octyl-6-yl; 2-aza-bicyclo[2.2.1]hept-6-yl; an amine having the formula NR6R7 where R6 and R7 are the each individually selected from hydrogen, unsubstituted and substituted alkyl having from 1 to 10 carbon atoms, cycloalkyl, alkene, carboxy substituted alkene, lower alkyl substituted at least once by cyano, alkyne, cycloalkyl, hydroxyl, 2-hydroxyethoxy, pyridine, piperidine, pyrrolidine, piperazine, morpholine, methylpiperazine, 1-Methylpyrrol, phenyl, phenyl substituted at least once by alkoxy, halogen, carboxyl, phenoxy, hydroxy, nitro, iodine, and mixtures thereof, imidazole, 5-nitropyridylamino, furan, benzo[1,3]dioxol-5-yl, indole, alkoxy substituted indole, diethylamino, alkoxy, carboxy, trifluoromethyl, lower alkyl, hydroxymethyl, and mixtures thereof, benzyl, phenyl, benzo[1,2,5]thiadiazol, pyridine, 1,2,4-triazole, and 3-oxo-cyclohex-1-en.
The following definitions apply to certain terms used herein.
The term xe2x80x9chalogenxe2x80x9d refers to fluorine, bromine, chlorine, and iodine atoms.
The term xe2x80x9chydroxylxe2x80x9d refers to the group xe2x80x94OH.
The term xe2x80x9cfuranxe2x80x9d refers to a five membered oxygen containing saturated or unsaturated heterocycle.
The term xe2x80x9coxoxe2x80x9d refers to the group xe2x95x90O.
The term xe2x80x9cthiolxe2x80x9d and xe2x80x9cmercaptoxe2x80x9d refers to the groups xe2x80x94SH, and xe2x80x94S(O)0-2, respectively.
The term xe2x80x9clower alkylxe2x80x9d refers to a cyclic, branched, or straight chain alkyl group of one to ten carbon atoms. This term is further exemplified by such groups as methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl, i-butyl (or 2-methylpropyl), cyclopropylmethyl, i-amyl, n-amyl, hexyl and the like.
The term xe2x80x9csubstituted lower alkylxe2x80x9d refers to lower alkyl as just described including one or more substituents such as hydroxyl, thiol, alkylthiol, halogen, alkoxy, amino, amido, carboxyl, cycloalkyl, substituted cycloalkyl, heterocycle, cycloheteroalkyl, substituted cycloheteroalkyl, acyl, carboxyl, aryl, substituted aryl, aryloxy, heteroaryl, substituted heteroaryl, arylalkyl, heteroarylalkyl, alkyl alkenyl, alkyl alkynyl, alkyl cycloalkyl, alkyl cycloheteroalkyl, and cyano. These groups may be attached to any carbon atom of the lower alkyl moiety.
The term xe2x80x9calkenylxe2x80x9d refers to a group xe2x80x94Rxe2x80x2Cxe2x95x90CRxe2x80x3Rxe2x80x2xe2x80x3 where Rxe2x80x2, Rxe2x80x3, Rxe2x80x2xe2x80x3 are each individually selected from hydrogen, halogen, lower alkyl, substituted lower alkyl, acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl or the like.
The term xe2x80x9calkynylxe2x80x9d refers to a group xe2x80x94Cxe2x89xa1Cxe2x80x94Rxe2x80x2; where Rxe2x80x2 is selected from hydrogen, halogen, lower alkyl, substituted lower alkyl, acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl or the like.
The term xe2x80x9calkyl alkenylxe2x80x9d refers to a group xe2x80x94Rxe2x80x94CRxe2x80x2xe2x95x90CRxe2x80x2xe2x80x3Rxe2x80x3xe2x80x3, where R is lower alkyl, or substituted lower alkyl, Rxe2x80x2, Rxe2x80x2xe2x80x3, Rxe2x80x3xe2x80x3 are each independently selected from hydrogen, halogen, lower alkyl, substituted lower alkyl, acyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl.
The term xe2x80x9calkyl alkynylxe2x80x9d refers to a group xe2x80x94RCxe2x89xa1CRxe2x80x2 where R is lower alkyl or substituted lower alkyl, Rxe2x80x2 is hydrogen, lower alkyl, substituted lower alkyl, acyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl.
The term xe2x80x9calkoxyxe2x80x9d refers to the group xe2x80x94OR, where R is lower alkyl, substituted lower alkyl, acyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroarylalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, or substituted cycloheteroalkyl.
The term xe2x80x9calkylthioxe2x80x9d denotes the group xe2x80x94SR, xe2x80x94S(O)n=1-2xe2x80x94R, where R is lower alkyl, substituted lower alkyl, aryl, substituted aryl, arylalkyl or substituted arylalkyl.
The term xe2x80x9cacylxe2x80x9d refers to groups xe2x80x94C(O)R, where R is hydrogen, lower alkyl, substituted lower alkyl, aryl, substituted aryl and the like.
The term xe2x80x9caryloxyxe2x80x9d refers to groups xe2x80x94OAr, where Ar is an aryl, substituted aryl, heteroaryl, or substituted heteroaryl group.
The term xe2x80x9caminoxe2x80x9d refers to the group NRRxe2x80x2, where R and Rxe2x80x2 may independently be hydrogen, lower alkyl, substituted lower alkyl, aryl, substituted aryl, heteroaryl, cycloalkyl, substituted heteroaryl, or acyl.
The term xe2x80x9camidoxe2x80x9d refers to the group xe2x80x94C(O)NRRxe2x80x2, where R and Rxe2x80x2 may independently be hydrogen, lower alkyl, substituted lower alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl.
The term xe2x80x9ccarboxylxe2x80x9d refers to the group xe2x80x94C(O)OR, where R may independently be hydrogen, lower alkyl, substituted lower alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl and the like.
The terms xe2x80x9carylxe2x80x9d and xe2x80x9cArxe2x80x9d refer to an aromatic carbocyclic group having at least one aromatic ring (e.g., phenyl or biphenyl) or multiple condensed rings in which at least one ring is aromatic, (e.g., 1,2,3,4-tetrahydronaphthyl, naphthyl, anthryl, or phenanthryl).
The term xe2x80x9csubstituted arylxe2x80x9d refers to aryl optionally substituted with one or more functional groups, e.g., halogen, lower alkyl, lower alkoxy, lower alkylthio, trifluoromethyl, amino, amido, carboxyl, hydroxyl, aryl, aryloxy, heterocycle, heteroaryl, substituted heteroaryl, nitro, cyano, alkylthio, thiol, sulfamido and the like.
The term xe2x80x9cheterocyclexe2x80x9d refers to a saturated, unsaturated, or aromatic carbocyclic group having a single ring (e.g., morpholino, pyridyl or furyl) or multiple condensed rings (e.g., naphthpyridyl, quinoxalyl, quinolinyl, indolizinyl or benzo[b]thienyl) and having at least one hetero atom, such as N, O, or S, within the ring, which can optionally be unsubstituted or substituted with, e.g., halogen, lower alkyl, alkoxy, lower alkylthio, trifluoromethyl, amino, amido, carboxyl, hydroxyl, aryl, aryloxy, heterocycle, heteroaryl, substituted heteroaryl, nitro, cyano, alkylthio, thiol, sulfamido and the like.
The term xe2x80x9cheteroarylxe2x80x9d refers to a heterocycle in which at least one heterocyclic ring is aromatic.
The term xe2x80x9csubstituted heteroarylxe2x80x9d refers to a heterocycle optionally substituted with one or more substituents including halogen, lower alkyl, lower alkoxy, lower alkylthio, trifluoromethyl, amino, amido, carboxyl, hydroxyl, aryl, aryloxy, heterocycle, heteroaryl, substituted heteroaryl, nitro, cyano, alkylthio, thiol, sulfamido and the like.
The term xe2x80x9carylalkylxe2x80x9d refers to the group xe2x80x94Rxe2x80x94Ar where Ar is an aryl group and R is lower alkyl or substituted lower alkyl group. Aryl groups can optionally be unsubstituted or substituted with, e.g., halogen, lower alkyl, alkoxy, alkylthio, trifluoromethyl, amino, amido, carboxyl, hydroxyl, aryl, aryloxy, heterocycle, heteroaryl, substituted heteroaryl, nitro, cyano, thiol, sulfamido and the like.
The term xe2x80x9cheteroalkylxe2x80x9d refers to the group xe2x80x94Rxe2x80x94Het where Het is a heterocycle group and R is a lower alkyl group. Heteroalkyl groups can optionally be unsubstituted or substituted with e.g., halogen, lower alkyl, lower alkoxy, lower alkylthio, trifluoromethyl, amino, amido, carboxyl, hydroxyl, aryl, aryloxy, heterocycle, heteroaryl, substituted heteroaryl, nitro, cyano, alkylthio, thiol, sulfamido and the like.
The term xe2x80x9cheteroarylalkylxe2x80x9d refers to the group xe2x80x94Rxe2x80x94HetAr where HetAr is a heteroaryl group and R is a lower alkyl or substituted lower alkyl. Heteroarylalkyl groups can optionally be unsubstituted or substituted with, e.g., halogen, lower alkyl, substituted lower alkyl, alkoxy, alkylthio, aryl, aryloxy, heterocycle, heteroaryl, substituted heteroaryl, nitro, cyano, alkylthio, thiol, sulfamido and the like.
The term xe2x80x9ccycloalkylxe2x80x9d refers to a divalent cyclic or polycyclic alkyl group containing 3 to 15 carbons. For polycyclic groups, these may be multiple condensed rings in which one of the distal rings may be aromatic (e.g., indanyl, tetrahydronaphthalene, etc. . . . ).
The term xe2x80x9csubstituted cycloalkylxe2x80x9d refers to a cycloalkyl group comprising one or more substituents with, e.g., halogen, lower alkyl, substituted lower alkyl, alkoxy, alkylthio, aryl, aryloxy, heterocycle, heteroaryl, substituted heteroaryl, nitro, cyano, alkylthio, thiol, sulfamido and the like.
The term xe2x80x9ccycloheteroalkylxe2x80x9d refers to a cycloalkyl group wherein one or more of the ring carbon atoms is replaced with a heteroatom (e.g., N, O, S or P).
The term xe2x80x9csubstituted cycloheteroalkylxe2x80x9d refers to a cycloheteroalkyl group as herein defined which contains one or more substituents, such as halogen, lower alkyl, lower alkoxy, lower alkylthio, trifluoromethyl, amino, amido, carboxyl, hydroxyl, aryl, aryloxy, heterocycle, heteroaryl, substituted heteroaryl, nitro, cyano, alkylthio, thiol, sulfamido and the like.
The term xe2x80x9calkyl cycloalkylxe2x80x9d refers to the group xe2x80x94Rxe2x80x94cycloalkyl where cycloalkyl is a cycloalkyl group and R is a lower alkyl or substituted lower alkyl. Cycloalkyl groups can optionally be unsubstituted or substituted with e.g. halogen, lower alkyl, lower alkoxy, lower alkylthio, trifluoromethyl, amino, amido, carboxyl, hydroxyl, aryl, aryloxy, heterocycle, heteroaryl, substituted heteroaryl, nitro, cyano, alkylthio, thiol, sulfamido and the like.
It is within the knowledge of one skilled in the art that stereoisomers of the compositions described herein as well as isomer and stereoisomers of components that comprise the compositions identified herein all fall within the scope of compositions that are useful in the therapeutic method of this invention.
If the compound useful in the method of this invention contains a basic group, an acid addition salt may be prepared. Acid addition salts of the compounds are prepared in a standard manner in a suitable solvent from the parent compound and an excess of acid, such as hydrochloric, hydrobromic, sulfuric, phosphoric, acetic, maleic, succinic, or methanesulfonic. If the final compound contains an acidic group, cationic salts may be prepared. Typically the parent compound is treated with an excess of an alkaline reagent, such as hydroxide, carbonate or alkoxide, containing the appropriate cation. Cations such as NA+, K+, Ca+2 and NH4+ are examples of cations present in pharmaceutically acceptable salts.
Compounds of formula (I) may be prepared by the following process. The process is characterized by the reaction of compounds of the general formula: 
in which R1 and R2 have the meaning given above, with compounds of the general formula: 
in which R3 and R4 have the meaning given above, and wherein ""Y represents halide, hydroxyl or O-acyl and wherein Y represents halide, preferably bromine. The reaction occurs in inert solvents and in the presence of base and/or auxiliaries, the later converted into compounds of the general formula: 
in which R1, R2, R3, R4 and Y have the meaning given above. These compounds are reacted with amines of the general formula HR5 in which R5 have the meanings given above, in inert solvents, and, if appropriate in the presence of base and/or auxiliaries.
The process according to the invention can be illustrated by way of example by the following reaction scheme: 
Suitable solvents for the process are customary organic solvents which do not change under the reaction conditions. These preferably include ethers such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether, or alcohols, for example methanol, ethanol, propanol, isopropanol, butanol, iso-butanol or tert-butanol, or hydrocarbons such as benzene, toluene, xylene, hexane, cyclohexane or petroleum fractions, or halogenated hydrocarbons such as dichloromethane, trichloromethane, tetrachloromethane, dichloroethylene, trichloroethylene or chlorobenzene, or ethyl acetate, triethylamine, pyridine, dimethylsulphoxide, dimethylformamide, hexamnethylphosphoramide, acetonitrile, acetone or nitromethane. It is also possible to use mixtures of the solvents mentioned. Dimethylformamide and dimethylsulphoxide are preferred.
Bases which can be employed for the process are in general inorganic or organic bases. These preferably include alkali metal hydroxides, for example sodium hydroxide or potassium hydroxide, alkaline earth metal hydroxides, for example barium hydroxide, alkali metal carbonates such as sodium carbonate or potassium carbonate, alkaline earth metal carbonates such as calcium carbonate, or alkali metal or alkaline earth metal alkoxides such as sodium or potassium methoxide, sodium or potassium ethoxide or potassium tert-butoxide, or organic amines (trialkyl(C1-C6)-amines) such as triethylamine, or heterocycles such as 1,4-diazabicyclo[2.2.2]octane (DABCO), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), pyridine, diaminopyridine, methylpiperidine or morpholine. It is also possible to employ as bases alkali metals such as sodium or their hydrides such as sodium hydride. Potassium carbonate is preferred.
The above mentioned bases can, if appropriate, also be employed as acid-binding auxiliaries. Suitable auxiliaries are also dehydrating reagents. These include, for example, carbodiimides such as diisopropylcarbodiimide, dicyclohexylcarbodiimide or N-(3-dimethylaminopropyl)-Nxe2x80x2-ethylcarbodiimide hydrochloride or carbonyl compounds such as carbonyldiimidazole or 1,2-oxazolium compounds such as 2-ethyl-5-phenyl-19 oxazolium-3-sulphonate or propanephosphonic anhydride or iso-butyl chloroformate or benzotriazolyloxy-tris-(dimethylamino)phosphonium hexafluorophosphate or diphenyl phosphoramidate or methane-sulphonyl chloride, if appropriate in the presence of bases such as triethylamine or N-ethylmorpholine or N-methylpiperidine or dicyclohexylcarbodiimide and N-hydroxysuccinimide.
The acid-binding agents and dehydrating reagents are in general employed in an amount from 0.5 to 3 mol, preferably from 1 to 1.5 mol, relative to 1 mol of the corresponding carboxylic acids. In general, the base is employed in an amount from 0.05 to 10 mol, preferably from 1 to 2 mol, relative to 1 mol of the compound of this invention.
The processes for manufacturing compounds according to the invention are in general carried out in a temperature of from about xe2x88x9230xc2x0 C. to about 110xc2x0 C., preferably from about xe2x88x9210xc2x0 C. to about 50xc2x0 C. The manufacturing processes are in general carried out at normal pressure. However, it is also possible to carry out the processes at elevated pressure or at reduced pressure (e.g. in a range from 0.5 to 5 bar).
The compounds described above (some of which are disclosed in Tables 1-2 below) are useful for treating mammalian disorders such as eating disorders, obesity, hypertension, depression, brain or bodily disorders, and any other disorder mediated by NPY and the related Y5 receptor. It is preferred that the method of this invention is used to treat eating disorders such as obesity and bulimia. Specifically, the method of this invention can be used to inhibit the onset of obesity and to mediate the appetite in order to control and to reduce obese mammals such as humans. It is most preferred that the method of this invention is used to treat obesity and eating disorders in humans.
The compounds of the present invention are useful for treating disorders mediated by NPY via the Y5 receptor in mammals. For purposes of this disclosure, mammals includes humans, livestock, zoo animals, laboratory animals, experimental animals and pets. Livestock and related animals include, mammals such as cattle, horses, sheep, pigs, goats, camels, water buffaloes, donkeys, rabbits, fallow deer, reindeer; fur-bearing animals such as mink, chinchilla and raccoon; birds such as chickens, geese, turkeys and ducks. Laboratory animals and experimental animals include mice, rats, guinea pigs, golden hamsters, and pets include dogs, cats, rats, mice, guinea pigs, pigs, and the like.
The compounds of this invention may be administered to mammals both prophylactically and therapeutically by any administration protocol that is capable of supplying at least one compound of this invention to a Y5 receptor. Non-limiting examples of useful administration protocols include orally, parenterally, dermally, transdermally, rectally, nasally or by any other suitable pharmaceutical composition administration protocol that is within the knowledge of one skilled in the art.
The amide compositions of this invention will be administered in suitable pharmaceutical dosage forms. The pharmaceutical dosage form will depend largely upon the administration protocol used. The term pharmaceutical dosage form refers to items such as tablets, capsules, liquids and powders, comprising Y5 receptor inhibitors of this invention alone or in the presence of one or more pharmaceutical excipients. The choice of additives such as excipients and adjuvants again will depend largely upon the chosen administration protocol. The compounds of this invention can also be incorporated into food products such as biscuits and cookies. In essence, the compositions can be used as a dietary supplement to reduce or inhibit appetite. Those skilled in the pharmaceutical arts will recognize a wide variety of formulations and vehicles for administering compositions of this invention.
The administration protocol will largely dictate the final form and composition of pharmaceutical dosage forms comprising the Y5 receptor antagonists of this invention. For example, internal administration of compounds of this invention is effected, orally, in the form of powders, tablets, capsules, pastes, drinks, granules, or solutions, suspensions and emulsions which can be administered orally, or boli, in medicated food, or in drinking water. Internal administration may also be accomplished using a timed release formulation including additives such as surfactant or starch coated capsules, or using a quick release formulation such as a freeze-dried fast dissolving tablet. Dermal administration is effected, for example, in the form of transdermal patches, spraying or pouring-on and spotting-on. Parenteral administration is effected, for example, in the form of injection (intramuscularly, subcutaneously, intravenously, intraperitoneally) or by implants.
Suitable pharmaceutical dosage forms incorporating the Y5 receptor antagonists of this invention include but are not limited to solutions such as solutions for injection, oral solutions, concentrates for oral administration after dilution, solutions for use on the skin or in body cavities, pour-on and spot-on formulations, gels; emulsions and suspension for oral or dermal administration and for injection; semi-solid preparations; formulations in which the active compound is incorporated in cream base or in an oil-in-water or water-in-oil emulsion base; solid preparations such as powders, premixes or concentrates, granules, pellets, tablets, boli, capsules; aerosols and inhalants, and shaped articles containing active compound.
Pharmaceutical dosage forms that are solutions may be administered by injection intravenously, intramuscularly and subcutaneously. Solutions for injection are prepared by dissolving the active compound in a suitable solvent and, if appropriate, adding adjuvants such as solubilizers, acids, bases, buffer salts, antioxidants and preservatives. The solutions are sterile-filtered and drawn off.
Alternatively, solutions including compositions of this invention may be administered orally. Concentrates of compositions of this invention are preferably administered orally only after diluting the concentrate to the administration concentration. Oral solutions and concentrates are prepared as described above in the case of the solutions for injection. Solutions for use on the skin are applied dropwise, brushed on, rubbed in, splashed on or sprayed on. These solutions are prepared as described above in the case of solutions for injection.
Gels are applied to the skin, or introduced into body cavities. Gels are prepared by treating solutions which have been prepared as described in the case of the solutions for injection with such an amount of thickener that a clear substance of cream-like consistency is formed, or by any other means known to one skilled in the art.
Pour-on and spot-on formulations are poured onto, or splashed onto, limited areas of the skin, the active compound penetrating the skin and acting systemically. Pour-on and spot-on formulations are prepared by dissolving, suspending or emulsifying the active compound in suitable solvents or solvent mixtures which are tolerated by the skin. If appropriate, other adjuvants such as colorants, resorption accelerators, antioxidants, light stabilizers, and tackifiers are added.
Emulsions can be administered orally, dermally or in the form of injections. Emulsions are either of the water-in-oil type or of the oil-in-water type. They are prepared by dissolving Y5 receptor antagonists either in the hydrophobic or in the hydrophilic phase and homogenizing the phase with a solvent of the opposite phase with the aid of suitable adjuvants such as emulsifiers, colorants, resorption accelerators, preservatives, antioxidants, light stabilizers, and viscosity-increasing substances.
Suspensions can be administered orally, dermally or in the form of injection. They are prepared by suspending the active compound in a liquid if appropriate with the addition of further adjuvants such as wetting agents, colorants, resorption accelerators, preservatives, antioxidants and light stabilizers.
The pharmaceutical compositions of this invention may include one or more additives in the form of pharmaceutically acceptable additives. Useful additives include solvents, solubilizers, preservatives, thickeners, wetting agents, colorants, resorption accelerators, antioxidants, light stabilizers, tackifiers, viscosity increasing substances, fillers, flavorings, lubricating agents, and any other pharmaceutical composition additive known to those skilled in the art.
The additive may be a solvent such as water, alcohols such as ethanol, butanol, benzyl alcohol, glycerol, propylene glycol, polyethylene glycols, N-methyl-pyrrolidone, alkanols, glycerol, aromatic alcohols such as benzyl alcohol, phenylethanol, phenoxyethanol, esters such as ethyl acetate, butyl acetate, benzyl benzoate, ethers such as alkylene glycol alkyl ethers such as dipropylene glycol mono-methyl ether, diethylene glycol mono-butyl ether, ketones such as acetone, methyl ethyl ketone, aromatic and/or aliphatic hydrocarbons, vegetable or synthetic oils, DMF, dimethylacetamide, N-methyl-pyrrolidone, 2,2-dimethyl4-oxy-methylene-1,3-dioxolane.
The following additives may be useful as solubilizers of the compositions of this invention: solvents which enhance solution of the active compound in the main solvent or which prevent its precipitation. Examples are polyvinylpyrrolidone, polyoxyethylated castor oil, polyoxyethylated sorbitan esters.
Useful preservatives are, for example, benzyl alcohol, trichlorobutanol, p-hydroxybenzoic esters, and n-butanol.
Useful thickeners include inorganic thickeners such as bentonite, colloidal silica, aluminum monostearate, organic thickeners such as cellulose derivatives, polyvinyl alcohols and their copolymers, acrylates and methacrylates.
Other liquids which may be useful in pharmaceutical dosage forms of this invention are, for example, homogeneous solvents, solvent mixtures, and wetting agents (dispersants) which are typically surfactants.
Useful colorants are all colorants which are non-toxic and which can be dissolved or suspended.
Useful resorption accelerators are DMSO, spreading oils such as isopropyl myristate, dipropylene glycol pelargonate, silicone oils, fatty acid esters, triglycerides, fatty alcohols.
Useful antioxidants are sulphites or metabisulphites such as potassium metabisulphite, ascorbic acid, butylhydroxytoluene, butylhydroxyanisole, tocopherol.
A useful light stabilizer is novantisolic acid.
Useful tackifiers include cellulose derivatives, starch derivatives, polyacrylates, natural polymers such as alginates, gelatin.
Useful emulsifiers include non-ionic surfactants such as polyoxyethylated castor oil, polyoxyethylated sorbitan monooleate, sorbitan monostearate, glycerol monostearate, polyoxyethyl stearate, alkylphenol polyglycol ethers; ampholytic surfactants such as Di-Na N-lauryl- beta -iminodipropionate or lecithin; anionic surfactants, such as Na-lauryl sulphate, fatty alcohol ether sulphates, the monoethanolamine salt of mono/dialkylpolyglycol ether orthophosphoric esters; cationic surfactants such as cetyltrimethylammonium chloride.
Useful viscosity-increasing substances and substances which stabilize a therapeutic emulsion include carboxymethylcellulose, methylcellulose and other cellulose and starch derivatives, polyacrylates, alginates, gelatin, gum Arabic, polyvinylpyrrolidone, polyvinyl alcohol, copolymers of methyl vinyl ether and maleic anhydride, polyethylene glycols, waxes, colloidal silica or mixtures of the substances mentioned.
To prepare solid pharmaceutical dosage forms, the active compound is mixed with suitable additives, if appropriate with the addition of adjuvants, and the mixture is formulated as desired. Examples of physiologically acceptable solid inert additives include sodium chloride, carbonates such as calcium carbonate, hydrogen carbonates, aluminum oxides, silicas, clays, precipitated or colloidal silicon dioxide, and phosphates. Examples of solid organic additives include sugars, cellulose, foods such as dried milk, animal meals, cereal meals and coarse cereal meals and starches. Other suitable additives include lubricants and gliding agents such as magnesium stearate, stearic acid, talc, bentonites; disintegrants such as starch or crosslinked polyvinylpyrrolidone; binders such as, starch, gelatin or linear polyvinylpyrrolidone; and dry binders such as microcrystalline cellulose.
In the pharmaceutical dosage forms described herein, the active compounds can be present in the form of a mixture with at least one other Y5 receptor antagonist compound. Alternatively, or in addition, the pharmaceutical dosage forms of the invention can, in addition to at least one Y5 receptor antagonist, include any pharmaceutical compound that is capable of treating any known malady or disorder where the administration of both together create no unacceptable adverse effects.
Methods for treating NPY mediated diseases and disorders comprises the administration of an effective quantity of the chosen compound or combinations thereof, preferably dispersed in a pharmaceutical dosage form. Ready-to-use pharmaceutical dosage forms of this invention contain the active compound in concentrations of from 10 ppm to 20 per cent by weight, and preferably of from 0.1 to 10 per cent by weight. Pharmaceutical dosage forms of this invention that are diluted prior to administration, preferably contain the active compound in concentrations of from 0.5 to 90 per cent by weight, and preferably of from 5 to 50 per cent by weight. In general, it has proved advantageous to administer amounts of approximately 0.01 mg to approximately 100 mg of active compound per kg of body weight per day to achieve effective results.
The amount and frequency of administration of pharmaceutical dosage forms comprising Y5 receptor antagonists of this invention will be readily determined by one skilled in the art depending upon, among other factors, the route of administration, age and condition of the patient. These dosage units may be administered one to ten times daily for acute or chronic disease. No unacceptable toxicological effects are expected when compounds of the invention are administered in accordance with the present invention.
The pharmaceutical dosage forms comprising Y5 receptor antagonists of this invention are made following the conventional techniques of pharmacy involving milling, mixing, granulation, and compressing, when necessary, for tablet forms; or milling, mixing and filling for hard gelatin capsule forms. When a liquid additive is used, the preparation will be in the form of a syrup, elixir, emulsion or an aqueous or non-aqueous suspension. Such a liquid formulation may be administered directly p.o. or filled into a soft gelatin capsule.
While the compositions described herein may be administered as described above, (i.e., intramuscular, intravenous and subcutaneous etc. . . . ), it is preferred that the method of this invention is achieved by administering the compound described herein orally. When the oral administration route is chosen, a larger quantity of reactive agent will be required to produce the same effect as a smaller quantity given for example parenterally. In accordance with good clinical practice, it is preferred to administer the compound according to this method at a concentration level that would produce effective therapeutic results without causing any harmful side effects.
The compositions of this invention have non-therapeutic utility as well. The compositions of this invention are useful as analytical standards for Y5 receptor agonist or antagonist assays.
Compounds 1-329 identified in the Examples and in Tables 1 and 2 below are believed heretofore to be unknown. Known compounds that may be useful in the novel therapeutic method of this invention are compounds 330-3662 disclosed in Table 4 below.